Skip to main content

Advertisement

SpringerLink
Log in

MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics

  • Original Article
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Multiple endocrine neoplasia type 2A (MEN2A) may be rarely associated with cutaneous lichen amyloidosis (CLA), a skin lesion located in the interescapular region. Here, we describe 3 MEN2A-related CLA kindred and perform a systematic review (SR) of the literature on clinical, biochemical and molecular characteristics of MEN2A-related CLA patients. Thirty-eight patients with MEN2A-related CLA followed at our institution were evaluated. The median age at MEN2A diagnosis in our cohort was 25 (13–41) years, 68 % were women and all harbored codon 634 RET mutations. The literature search resulted in 20 publications that contributed with 25 MEN2A families and 214 individuals. The mean age of MEN2A diagnosis was 31 ± 17 years, with 77 % women. The mean age reported by patients to initial skin lesion suggestive to CLA was 20 ± 13 years. All but two kindred harbored mutations at codon 634: C634R 7 kindred (35 %), C634Y 5 kindred (25 %), C634W 3 kindred (15 %), C634G 1 kindred (5 %), V804M 1 kindred (5 %) and S891A 1 kindred (5 %). Most interesting, the standardized CLA prevalence was higher in women (2.3/1.0, P < 0.005). The overall reported prevalence of medullary thyroid carcinoma, CLA, pheochromocytoma and hyperparathyroidism was 94, 51, 30 and 16 %, respectively. SR of literature indicates that MEN2A-related CLA is more frequent in women and presents a high penetrance, being the second most frequent manifestation of the syndrome, preceded only by MTC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Davies L, Welch HG (2006) Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 295(18):2164–2167. doi:10.1001/jama.295.18.2164

    Article  CAS  PubMed  Google Scholar 

  2. Wells SA Jr, Asa SL, Dralle H et al (2015) Revised american thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid Off J Am Thyroid Assoc 25(6):567–610. doi:10.1089/thy.2014.0335

    Article  Google Scholar 

  3. Wells SA Jr, Pacini F, Robinson BG, Santoro M (2013) Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab 98(8):3149–3164. doi:10.1210/jc.2013-1204

    Article  CAS  PubMed  Google Scholar 

  4. Maia AL, Siqueira DR, Kulcsar MA, Tincani AJ, Mazeto GM, Maciel LM (2014) Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arquivos brasileiros de endocrinologia e metabologia 58(7):667–700

    Article  PubMed  Google Scholar 

  5. Mathew CG, Chin KS, Easton DF et al (1987) A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 328(6130):527–528. doi:10.1038/328527a0

    Article  CAS  PubMed  Google Scholar 

  6. Donis-Keller H, Dou S, Chi D et al (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2(7):851–856

    Article  CAS  PubMed  Google Scholar 

  7. Mulligan LM, Kwok JB, Healey CS et al (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363(6428):458–460. doi:10.1038/363458a0

    Article  CAS  PubMed  Google Scholar 

  8. Punales MK, Graf H, Gross JL, Maia AL (2003) RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab 88(6):2644–2649. doi:10.1210/jc.2002-021422

    Article  CAS  PubMed  Google Scholar 

  9. Wells SA Jr, Asa SL, Dralle H et al (2015) Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25(6):567–610. doi:10.1089/thy.2014.0335

    Article  PubMed  PubMed Central  Google Scholar 

  10. Maia AL, Gross JL, Puñales MK (2005) Neoplasia Endócrina Múltipla Tipo 2. Arq Bras Endocrinol Metab 49(5):725–734. doi:10.1590/S0004-27302005000500013

    Article  Google Scholar 

  11. Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA (1989) Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med 111(10):802–806

    Article  CAS  PubMed  Google Scholar 

  12. Kousseff BG, Espinoza C, Zamore GA (1991) Sipple syndrome with lichen amyloidosis as a paracrinopathy: pleiotropy, heterogeneity, or a continuous gene? J Am Acad Dermatol 25:651–657

    Article  CAS  PubMed  Google Scholar 

  13. de Groot JWB, Links TP, Plukker JTM, Lips CJM, Hofstra RMW  (2006) RET as a diagnostic and therapeutic target in sporadic and hereditary Endocrine tumors. Endocr Rev 27(5):535–560. doi:10.1210/er.2006-0017

    Article  PubMed  Google Scholar 

  14. Ferrer JP, Halperin I, Conget JI et al (1991) Primary localized cutaneous amyloidosis and familial medullary thyroid carcinoma. Clin Endocrinol 34(6):435–439

    Article  CAS  Google Scholar 

  15. Lemos MC, Carrilho F, Rodrigues FJ, Carvalheiro M, Regateiro FJ, Ruas MMA (2003) Caracterização Molecular de uma Família com NEM2A e suas Implicações Clínicas. Acta Méd Port 16:245–250

    CAS  PubMed  Google Scholar 

  16. Gullu S, Gursoy A, Erdogan MF, Dizbaysak S, Erdogan G, Kamel N (2005) Multiple endocrine neoplasia type 2A/localized cutaneous lichen amyloidosis associated with malignant pheochromocytoma and ganglioneuroma. J Endocrinol Invest 28(8):734–737

    Article  CAS  PubMed  Google Scholar 

  17. Osada D, Viegas SF, Shah MA, Morris RP, Patterson RM (2003) Comparison of different distal radius dorsal and volar fracture fixation plates: a biomechanical study. J Hand Surg 28(1):94–104. doi:10.1053/jhsu.2003.50016

    Article  Google Scholar 

  18. Tanaka A, Arita K, Lai-Cheong JE, Palisson F, Hide M, McGrath JA (2009) New insight into mechanisms of pruritus from molecular studies on familial primary localized cutaneous amyloidosis. Br J Dermatol 161(6):1217–1224. doi:10.1111/j.1365-2133.2009.09311.x

    Article  CAS  PubMed  Google Scholar 

  19. Breathnach SM (1988) Amyloid and amyloidosis. J Am Acad Dermatol 18(1 Pt 1):1–16

    Article  CAS  PubMed  Google Scholar 

  20. Pacini F, Fugazzola L, Bevilacqua G, Viacava P, Nardini V, Martino E (1993) Multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis: description of a new family. J Endocrinol Invest 16(4):295–296

    Article  CAS  PubMed  Google Scholar 

  21. Verga U, Fugazzola L, Cambiaghi S et al (2003) Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol 59(2):156–161

    Article  CAS  Google Scholar 

  22. Hong J, Buddenkotte J, Berger TG, Steinhoff M (2011) Management of itch in atopic dermatitis. Semin Cutan Med Surg 30(2):71–86. doi:10.1016/j.sder.2011.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Singh DN, Gupta S, Agarwal A (2012) Cutaneous lichen amyloidosis associated with multiple endocrine neoplasia type 2A: an early clinical marker. World J Endocr Surg 4(1):41. doi:10.5005/jp-journals-10002-1092

    Google Scholar 

  24. Rothberg AE, Raymond VM, Gruber SB, Sisson J (2009) Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid Off J Am Thyroid Assoc 19(6):651–655. doi:10.1089/thy.2009.0021

    Article  CAS  Google Scholar 

  25. Qi XP, Zhao JQ, Chen ZG et al (2015) RET mutation p.S891A in a Chinese family with familial medullary thyroid carcinoma and associated cutaneous amyloidosis binding OSMR variant p.G513D. Oncotarget 6(32):33993–34003. doi:10.18632/oncotarget.499

    PubMed  PubMed Central  Google Scholar 

  26. Robinson MF, Furst EJ, Nunziata V et al (1992) Characterization of the clinical features of five families with hereditary primary cutaneous lichen amyloidosis and multiple endocrine neoplasia type 2. Henry Ford Hosp Med J 40(3–4):249–252

    CAS  PubMed  Google Scholar 

  27. Takahashi M, Asai N, Iwashita T, Isomura T, Miyazaki K, Matsuyama M (1993) Characterization of the ret proto-oncogene products expressed in mouse L cells. Oncogene 8(11):2925–2929

    CAS  PubMed  Google Scholar 

  28. Lin SF, Huang YY, Lin JD, Chou TC, Hsueh C, Wong RJ (2012) Utility of a PI3K/mTOR inhibitor (NVP-BEZ235) for thyroid cancer therapy. PLoS One 7(10):e46726. doi:10.1371/journal.pone.0046726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tamburrino A, Molinolo AA, Salerno P et al (2012) Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases. Clin Cancer Res 18(13):3532–3540. doi:10.1158/1078-0432.CCR-11-2700

    Article  CAS  PubMed  Google Scholar 

  30. Seri M, Celli I, Betsos N, Claudiani F, Camera G, Romeo G (1997) A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. Clin Genet 51(2):86–90

    Article  CAS  PubMed  Google Scholar 

  31. Hofstra RM, Sijmons RH, Stelwagen T et al (1996) RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia. J Invest Dermatol 107(2):215–218

    Article  CAS  PubMed  Google Scholar 

  32. Lee DD, Huang JY, Wong CK, Gagel RF, Tsai SF (1996) Genetic heterogeneity of familial primary cutaneous amyloidosis: lack of evidence for linkage with the chromosome 10 pericentromeric region in Chinese families. J Invest Dermatol 107(1):30–33

    Article  CAS  PubMed  Google Scholar 

  33. Birla S, Singla R, Sharma A, Tandon N (2014) Rare manifestation of multiple endocrine neoplasia type 2A & cutaneous lichen amyloidosis in a family with RET gene mutation. Indian J Med Res 139(5):779–781

    PubMed  PubMed Central  Google Scholar 

  34. Abdullah F, Udelsman R (2004) Cutaneous lichen amyloidosis in a family with familial medullary thyroid cancer. Surgery 135(5):563–564. doi:10.1016/S0039

    Article  PubMed  Google Scholar 

  35. Vieira AE, Mello MP, Elias LL et al (2002) Molecular and biochemical screening for the diagnosis and management of medullary thyroid carcinoma in multiple endocrine neoplasia type 2A. Horm Metab Res 34(4):202–206. doi:10.1055/s-2002-26712

    Article  CAS  PubMed  Google Scholar 

  36. Karga HJ, Karayianni MK, Linos DA, Tseleni SC, Karaiskos KD, Papapetrou PD (1998) Germ line mutation analysis in families with multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma. Eur J Endocrinol 139(4):410–415

    Article  CAS  PubMed  Google Scholar 

  37. Ceccherini I, Romei C, Barone V et al (1994) Identification of the Cys634– > Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis. J Endocrinol Invest 17(3):201–204

    Article  CAS  PubMed  Google Scholar 

  38. Nunziata V, Giannattasio R, Di Giovanni G, D’Armiento MR, Mancini M (1989) Hereditary localized pruritus in affected members of a kindred with multiple endocrine neoplasia type 2A (Sipple’s syndrome). Clin Endocrinol 30(1):57–63

    Article  CAS  Google Scholar 

  39. Donovan DT, Levy ML, Furst EJ et al (1989) Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type 2A: a new variant. Henry Ford Hosp Med J 37(3–4):147–150

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundacão de Amparo Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE).

Author information

Author notes

    Authors and Affiliations

    1. Thyroid Section, Endocrine Division, Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos 2350, Porto Alegre, RS, 90035-003, Brazil

      Jessica Oliboni Scapineli, Lucieli Ceolin, José Miguel Dora & Ana Luiza Maia

    2. Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil

      Márcia Khaled Puñales

    Authors
    1. Jessica Oliboni Scapineli
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Lucieli Ceolin
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Márcia Khaled Puñales
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. José Miguel Dora
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ana Luiza Maia
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Ana Luiza Maia.

    Ethics declarations

    Conflict of interest

    The authors declare no competing financial interests exist that could be perceived as prejudicing the impartiality of the research reported.

    Additional information

    Jessica Oliboni Scapineli and Lucieli Ceolin have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Scapineli, J.O., Ceolin, L., Puñales, M.K. et al. MEN 2A-related cutaneous lichen amyloidosis: report of three kindred and systematic literature review of clinical, biochemical and molecular characteristics. Familial Cancer 15, 625–633 (2016). https://doi.org/10.1007/s10689-016-9892-6

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10689-016-9892-6

    Keywords

    Search

    Navigation